Novel JAK1 Inhibitor Reduced Treatment Failures in Active Noninfectious Uveitis

An investigational Janus kinase 1 (JAK1) preferential inhibitor reduced the risk of treatment failure among patients with active noninfectious uveitis, the phase II randomized HUMBOLDT trial showed.

Though the trial was stopped early, 37.5% of patients with active noninfectious intermediate uveitis, posterior uveitis, or panuveitis who received filgotinib experienced treatment failure by week 24 compared with 67.6% of those who received placebo (P=0.006), reported Sunil Srivastava, MD, of Cole Eye Institute at the Cleveland Clinic, and colleagues in JAMA Ophthalmology.

“The drug has the ability to help patients stabilize and not have recurrence of disease,” co-author Quan Dong Nguyen, MD, MSc, of Byers Eye Institute at Stanford University in Palo Alto, California, told MedPage Today. “If a JAK inhibitor can show efficacy and safety, there’s no reason why it cannot be another first-line steroid-sparing treatment.”

As the study authors noted, anterior uveitis — the most common type — can frequently be managed with topical corticosteroids. “Noninfectious intermediate uveitis, posterior uveitis, and panuveitis subtypes are more challenging to control, requiring systemic or intravitreal corticosteroid therapies such as prednisone and triamcinolone acetonide, respectively,” Srivastava and team wrote.

However, Nguyen said, “the long-term use of systemic corticosteroids will lead to complications such as diabetes, hypertension, mood changes, suicidal ideation, and others. We cannot keep patients on long-term high-dose steroids — more than 7.5 mg of prednisone or equivalent daily.”

This trial is apparently the first study of a JAK inhibitor in uveitis, which in idiopathic cases “is presumed to be immune mediated,” and linked to conditions that are associated with activation of signaling pathways involving JAK, like inflammatory bowel disease.

Filgotinib is not FDA-approved, but it is indicated to treat rheumatoid arthritis and ulcerative colitis in the European Union, the U.K., and other countries. Adalimumab (Humira) is the only FDA-approved non-steroid treatment for these types of uveitis.

Sruthi Arepalli, MD, of Emory University School of Medicine in Atlanta, told MedPage Today that better treatments for noninfectious uveitis are needed.

“The outcomes of the medication are favorable, but there is still a high rate of treatment failure,” she said. “Uveitis can be visually devastating. Undertreatment or failure to treat the disease can result in blindness and lack of functionality in patients.”

This study’s findings are promising, she added, but more research is needed “before I can recommend using the drug off-label.”

The goal of the study was to see whether the disease would flare up after systemic corticosteroids had been tapered off and the patients had been started on either filgotinib or placebo, Nguyen said. The study began in 2017 and was supposed to have 248 participants, but the study funder cancelled the trial partway through in 2020. The 72 patients enrolled at that time were allowed to continue. Seventeen stopped the study drug, and 55 completed the trial.

The cessation of the trial due to “business reasons” was “unfortunate,” Nguyen said. But he noted that the ongoing NEPTUNE trial is examining a JAK1/TYK2 inhibitor, brepocitinib, in uveitis, and recently reported positive phase II findings; a phase III trial of brepocitinib is planned.

“The HUMBOLDT study did not have any severe adverse events that were truly deemed to be related to the study drug and not tolerable,” Nguyen said. “Similarly, the NEPTUNE study of brepocitinib did not have any severe adverse events that were deemed study drug-related and intolerable. But the studies have been small, and more data are needed.”

In HUMBOLDT, adverse events were reported in 81.1% of patients who received filgotinib and in 68.6% of those who received placebo. Serious adverse events were reported in 13.5% and 5.7%, respectively. No deaths were reported during the trial.

Edmund Tsui, MD, of the University of California Los Angeles and a co-investigator in the NEPTUNE study, cautioned that “looking at the class of JAK inhibitors as a whole, we have to be mindful that there is an increased risk of serious infections, as well as malignancies, cardiovascular events, thrombosis, or death, although none of the latter were reported in [the HUMBOLDT] trial.”

This double-masked study was conducted from July 2017 to April 2021 at 26 centers in seven countries. The 72 participants in the study with active noninfectious intermediate uveitis, posterior uveitis, or panuveitis despite at least 2 weeks of treatment with oral prednisone were randomly assigned 1:1 to receive filgotinib 200 mg or placebo orally once daily for up to 52 weeks. Mean age was 46, and 59.7% were women.

Treatment failure was defined as a composite endpoint represented by assessment of the presence of chorioretinal and/or retinal vascular lesions, best-corrected visual acuity, and anterior chamber cell and vitreous haze grades.

As for limitations, Srivastava and colleagues noted that, in addition to the study being halted before ending, it was unclear “whether filgotinib could offer significant anti-inflammatory control as a monotherapy during an active flare period owing to the protocol-defined prednisone taper, although this is a minor point considering that clinicians typically regard corticosteroids as a bridge to biologics.”

Randy Dotinga is a freelance medical and science journalist based in San Diego.

Disclosures

This trial was funded by Gilead Sciences.

Srivastava reported receiving research grants from Regeneron, EyePoint, Allergan, and Gilead, and receiving consultancy fees from Adverum, Aura, Bausch, Gilead, jCyte, Novartis, Optos, Regeneron, and Zeiss.

Nguyen reported serving on the scientific advisory board for Genentech, Kriya, Novartis, Regeneron, and Santen, among others, and serving on the data safety and monitoring board for Alvotech and Bellus Health.

Other co-authors also reported multiple relationships with industry.

Arepalli reported consulting for AbbVie and Alimera Sciences.

Tsui reported consulting for Oculis, EyePoint, and Kowa, and receiving grant funding from the NIH/National Eye Institute, Pfizer, and Cylite. He is a site investigator for clinical trials run by Priovant, Acelyrin, Tarsier, Alumis, and Genentech/Roche.

Primary Source

JAMA Ophthalmology

Source Reference: Srivastava SK, et al “Filgotinib in active noninfectious uveitis: the HUMBOLDT randomized clinical trial” JAMA Ophthalmol 2024; DOI: 10.1001/jamaophthalmol.2024.2439.

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